A Novel Mechanism of Monoethylhexyl Phthalate in Lipid Accumulation via Inhibiting Fatty Acid Beta-Oxidation on Hepatic Cells

Monoethylhexyl
phthalate (MEHP) is one of the main active metabolites
of the plasticizer di­(2-ethylhexyl) phthalate. It has been known that
MEHP has an impact on lipolysis; however, its mechanism on the cellular
lipid metabolism remains largely unclear. Here, we first utilized
global lipid profiling to fully characterize the lipid synthesis and
degradation pathways upon MEHP treatment on hepatic cells. Meanwhile,
we further identified the possible MEHP-targeted proteins in living
cells using the cellular thermal shift assay (CETSA) method. The lipidomics
results showed that there was a significant accumulation of fatty
acids and other lipids in the cell. The CETSA identified 18 proteins
and fatty acid β-oxidation inhibition pathways that were significantly
perturbed. MEHP’s binding with selected proteins HADH and HSD17B10
was further evaluated using molecule docking, and results showed that
MEHP has higher affinities as compared to endogenous substrates, which
was further experimentally confirmed in the surface plasma resonance
interaction assay. In summary, we found a novel mechanism for MEHP-induced
lipid accumulation, which was probably due to its inhibitive effects
on the enzymes in fatty acid β-oxidation. This mechanism substantiates
the public concerns on the high exposure level to plasticizers and
their possible role as an obesogen.